title: A novel diol-derivative of chalcone produced by bioconversion, 3-(2,3-dihydroxyphenyl)-1-phenylpropan-1-one, activates PKA/MEK/ERK signaling and antagonizes Abeta-inhibition of the cascade in cultured rat CNS neurons.
abstract: Chalcone compounds have been widely studied for their anti-inflammatory, anti-pyretic, anti-invasive and anti-proliferative activities in various cell lines. However, their effects on the central nervous system (CNS) are still largely unexplored. We have recently developed a bioconversion system using a recombinant Escherichia coli that enables us to produce chemical compounds that are naturally rare and usually difficult to chemically synthesize. One such compound is 3-(2,3-dihydroxyphenyl)-1-phenylpropan-1-one, a novel chalcone-diol. Here we show, for the first time, that the chalcone-diol enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) in a time- and concentration-dependent manner in cultured cortical neurons. Also, this chalcone-diol increased intracellular cyclic AMP (cAMP) concentration, thereby enhancing phosphorylation of ERK and cAMP-response element-binding protein (CREB), and CRE-mediated transcription via the cAMP-dependent protein kinase (PKA)/mitogen-activated protein kinase/ERK kinase (MEK) pathway in cultured rat hippocampal neurons. Recent studies have demonstrated that PKA/CREB-dependent signaling, which is required for long-term potentiation, is inhibited by sublethal concentrations of amyloid beta-peptide (Abeta) in cultured hippocampal neurons. After treatment with the chalcone-diol at 50 muM prior to treatment with a sublethal concentration of Abeta(1-42), the Abeta(1-42)-induced inhibition of phosphorylation of PKA substrates and CREB was prevented in cultured hippocampal neurons, indicating the potential for protection against the Abeta-induced impairment of PKA/CREB signaling observed in Alzheimer's disease. Therefore, these results suggest that our present study provides a new approach for discovering novel lead compounds for the treatment of neurodegenerative CNS diseases associated with impaired PKA/CREB signaling, including Alzheimer's disease.
authors.affiliation: Department of Pharmacotherapy, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Sendai, Japan.
authors.forename: Md
authors.initials: M
authors.lastname: Al Rahim
authors.forename: Akira
authors.initials: A
authors.lastname: Nakajima
authors.forename: Norihiko
authors.initials: N
authors.lastname: Misawa
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Shindo
authors.forename: Kyoko
authors.initials: K
authors.lastname: Adachi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Shizuri
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ohizumi
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamakuni
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011427:Propiophenones / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: C539141:3-(2,3-dihydroxyphenyl)-1-phenylpropan-1-one; D016229:Amyloid beta-Peptides; D017362:Cyclic AMP Response Element-Binding Protein; D011427:Propiophenones; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases